Copper homeostasis and cuproptosis in cancer immunity and therapy.

Copper is an essential nutrient for maintaining enzyme activity and transcription factor function. Excess copper results in the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), which correlates to the mitochondrial tricarboxylic acid (TCA) cycle, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cuproptosis exerts an indispensable role in cancer progression, which is considered a promising strategy for cancer therapy. Cancer immunotherapy has gained extensive attention owing to breakthroughs in immune checkpoint blockade; furthermore, cuproptosis is strongly connected to the modulation of antitumor immunity. Thus, a thorough recognition concerning the mechanisms involved in the modulation of copper metabolism and cuproptosis may facilitate improvement in cancer management. This review outlines the cellular and molecular mechanisms and characteristics of cuproptosis and the links of the novel regulated cell death modality with human cancers. We also review the current knowledge on the complex effects of cuproptosis on antitumor immunity and immune response. Furthermore, potential agents that elicit cuproptosis pathways are summarized. Lastly, we discuss the influence of cuproptosis induction on the tumor microenvironment as well as the challenges of adding cuproptosis regulators to therapeutic strategies beyond traditional therapy.

Compensatory thickening of cortical thickness in early stage of schizophrenia.

Brain structural abnormality has been observed in the prodromal and early stages of schizophrenia, but the mechanism behind it is not clear. In this study, to explore the association between cortical abnormalities, metabolite levels, inflammation levels and clinical symptoms of schizophrenia, 51 drug-naive first-episode schizophrenia (FES) patients, 51 ultra-high risk for psychosis (UHR), and 51 healthy controls (HC) were recruited. We estimated gray matter volume (GMV), cortical thickness (CT), concentrations of different metabolites, and inflammatory marks among four groups (UHR converted to psychosis [UHR-C], UHR unconverted to psychosis [UHR-NC], FES, HC). UHR-C group had more CT in the right lateral occipital cortex and the right medial orbito-frontal cortex (rMOF), while a significant reduction in CT of the right fusiform cortex was observed in FES group. UHR-C group had significantly higher concentration of IL-6, while IL-17 could significantly predict CT of the right fusiform and IL-4 and IL-17 were significant predictors of CT in the rMOF. To conclude, it is reasonable to speculate that the increased CT in UHR-C group is related to the inflammatory response, and may participate in some compensatory mechanism, but might become exhaustive with the progress of the disease due to potential neurotoxic effects.

Interfacial Mass Diagnostics: Quantitative Perspective on Construction and Mechanism Understanding of Dye-Sensitized, Perovskite and Quantum Dots Solar Cells.

Dye-sensitized solar cells (DSSCs), quantum dot-sensitized solar cells (QDSSCs) and perovskite solar cells (PSCs) have attracted wide attention. DSSCs, QDSSCs and PSCs can be prepared by liquid phase or solid phase, which causes a certain range of interface micro-mass changes during preparation. In addition, the photoelectric conversion process occurring inside the device also inevitably causes interface micro-mass changes. Interpretation of these interface micro-mass changes can help to optimize the cell structure, improve the stability and performance repeatability of the device, as well as directly or indirectly infer, track and predict the internal photoelectric conversion mechanism of the device. Quartz crystal microbalance (QCM) is a powerful tool for studying surface mass changes, extending this technology to the fields of solar cells to directly obtain interface micro-mass changes, which makes the research more in-depth and opens up a new perspective for explaining the basic principles of solar cells. This review summarizes the research progress of QCM application in DSSCs, QDSSCs and PSCs in recent years, and explores the challenges and new opportunities of QCM application in new solar cells in the future.

DNA demethylase ALKBH1 promotes adipogenic differentiation via regulation of HIF-1 signaling.

DNA N6-adenine methylation (6mA), as a novel adenine modification existing in eukaryotes, shows essential functions in embryogenesis and mitochondrial transcriptions. ALKBH1 is a demethylase of 6mA and plays critical roles in osteogenesis, tumorigenesis, and adaptation to stress. However, the integrated biological functions of ALKBH1 still require further exploration. Here, we demonstrate that knockdown of ALKBH1 inhibits adipogenic differentiation in both human mesenchymal stem cells (hMSCs) and 3T3-L1 preadipocytes, while overexpression of ALKBH1 leads to increased adipogenesis. Using a combination of RNA-seq and N6-mA-DNA-IP-seq analyses, we identify hypoxia-inducible factor-1 (HIF-1) signaling as a crucial downstream target of ALKBH1 activity. Depletion of ALKBH1 leads to hypermethylation of both HIF-1α and its downstream target GYS1. Simultaneous overexpression of HIF-1α and GYS1 restores the adipogenic commitment of ALKBH1-deficient cells. Taken together, our data indicate that ALKBH1 is indispensable for adipogenic differentiation, revealing a novel epigenetic mechanism that regulates adipogenesis.

Periplaneta americana extract promotes osteoblast differentiation of human alveolar bone marrow mesenchymal stem cells.

OBJECTIVES: This study aims to investigate the effects of Traditional Chinese medicine, Periplaneta americana extract (PAE), on osteoblast differentiation of human alveolar bone marrow-derived mesenchymal stem cells (hABMMSCs). MATERIALS AND METHODS: Human alveolar bone marrow-derived mesenchymal stem cells were treated with different concentrations of PAE. Cell Counting Kit-8 (CCK-8) assay and transwell migration assay were conducted to evaluate cell proliferation and migration, respectively. Alkaline phosphatase (ALP) staining, ALP activity assay, and Alizarin red S staining were performed to detect osteogenesis in hABMMSCs. In addition, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) assay were performed to evaluate expression levels of osteogenic markers. Finally, RNA sequencing analysis and WB were carried out to elucidate the underlying mechanism. RESULTS: A total of 0.1 mg/ml PAE promoted cell proliferation and migration. PAE also increased ALP activity and mineralized nodule formation of hABMMSCs. In addition, PAE upregulated the expression of osteogenesis-related genes (RUNX2, COL1A1, and BGLAP). RNA-sequencing analysis revealed that PAE activated the focal adhesion signaling pathway. Treatment with Defactinib, an inhibitor of FAK, attenuated the effects induced by PAE. CONCLUSIONS: PAE could enhance osteoblast differentiation of hABMMSCs through focal adhesion signaling pathway, suggesting a therapeutic potential for the alveolar bone defect.

Ubiquitin-specific protease USP34 controls osteogenic differentiation and bone formation by regulating BMP2 signaling.

The osteogenic differentiation of mesenchymal stem cells (MSCs) is governed by multiple mechanisms. Growing evidence indicates that ubiquitin-dependent protein degradation is critical for the differentiation of MSCs and bone formation; however, the function of ubiquitin-specific proteases, the largest subfamily of deubiquitylases, remains unclear. Here, we identify USP34 as a previously unknown regulator of osteogenesis. The expression of USP34 in human MSCs increases after osteogenic induction while depletion of USP34 inhibits osteogenic differentiation. Conditional knockout of Usp34 from MSCs or pre-osteoblasts leads to low bone mass in mice. Deletion of Usp34 also blunts BMP2-induced responses and impairs bone regeneration. Mechanically, we demonstrate that USP34 stabilizes both Smad1 and RUNX2 and that depletion of Smurf1 restores the osteogenic potential of Usp34-deficient MSCs in vitro Taken together, our data indicate that USP34 is required for osteogenic differentiation and bone formation.

Adsorption Thermodynamic and Kinetic Mechanism of Substrate-Induced Molecular Geometry Orientation.

N719 dye (cis-[Ru(4-carboxy-4'-carboxylate-2,2'-bipyridine)2(NCS)2]) contains two carboxylic acid/carboxylate groups and two isothiocyanato (NCS) ligands and exhibit different spatial adsorption orientations during adsorption on different substrate surfaces. However, the effect of spatially adsorption orientations on the adsorption process has been rarely reported. This paper presents a detailed study of the adsorption kinetics and thermodynamics of N719 molecules based on a quartz crystal microbalance under variable temperature conditions using TiO2 or Au substrate surfaces to induce changes in the geometrical orientation molecules. This work also reveals the adsorption properties of carboxylate groups and NCS ligands acting as anchoring groups. Research results have shown that the surface N719 molecular density of the TiO2 substrate is higher than that of the Au substrate. Adsorption kinetics have shown that the adsorption rate of N719 molecules on the Au substrate surface with NCS ligands as anchor groups is slightly higher than that of carboxylate as the anchor groups on the TiO2 substrate surface, and in the case of the former adsorption mode, the desorption is more pronounced. Under two different spatial orientation adsorption modes, both exhibit physical adsorption. The thermodynamics of molecular adsorption with different spatial orientations show that all adsorption processes are spontaneous and endothermic. This work is beneficial for understanding the mechanism of adsorption of dye molecules, dye molecule synthesis method, ligand selection, and improvement of device efficiency.

Unloading of occlusal force aggravates alveolar bone loss in periodontitis.

BACKGROUND AND OBJECTIVE: Periodontitis (PD), a chronic infectious inflammatory disease initiated by bacteria, is associated with several local contributing factors including occlusal trauma. Previous studies have found that the traumatic occlusal force could aggravate alveolar bone loss during PD. However, the effect of reduced occlusal force during PD remains unclear. This study aimed to explore the effect of occlusal force unloading on PD onset and progression and its underlying mechanism as an effort to provide restoration suggestions for PD patients with dentition defect in clinic. This study might also propose occlusal force unloading could be a new local contributing factor for PD. MATERIALS AND METHODS: C57BL/6 mice were used to establish a PD model by the ligation of 5-0 silk around the mandibular left first molar (PD group) and an unloading experiment model by the extraction of their left maxillary first molar (EX group). The THP-1-derived macrophages were used to verify in vivo results. RESULTS: Micro-CT scanning and H&E staining results consistently showed that PD + EX group experienced the most severe alveolar bone resorption as compared to PD group and control group. Further RNA-sequencing analysis suggested that occlusal force unloading significantly enhanced osteoclastic resorption, inhibited osteoblastic activity, and promotes M1 and M2 macrophages polarization. Immunofluorescence staining (IF) results showed that compared with the PD group, PD + EX group significantly increased the ratio of M1/M2 polarization. Similar results were observed by RT-qPCR and IF in vitro: removal of compressive force led to an increased ratio of M1/M2 polarization in LPS-stimulated THP-1-derived macrophages. CONCLUSIONS: Our study demonstrated that occlusal force unloading aggravates bone resorption by increasing the ratio of M1/M2 macrophages polarization during PD, suggesting a previously unknown local contributing factor for PD, and providing a novel insight for dentists to restore missing teeth as an effort to maintain remaining dentition.

Heterogeneity induced splay state of amplitude envelope in globally coupled oscillators.

Splay states of the amplitude envelope are stably observed as a heterogenous node is introduced into the globally coupled identical oscillators with repulsive coupling. With the increment of the frequency mismatches between the heterogenous nodes and the rest identical globally coupled oscillators, the formal stable splay state based on the time series becomes unstable, while a splay state based on the new-born amplitude envelopes of time series is stably observed among the rest identical oscillators. The characteristics of the splay state based on the amplitude envelope are numerically and theoretically presented for different parameters of the coupling strength ϵ and the frequency mismatches Δω for small coupling strength and large frequency mismatches. We expect that all these results could reveal the generality of splay states in coupled nonidentical oscillators and help to understand the rich dynamics of amplitude envelopes in multidisciplinary fields.

Hyperglycemia accelerates inflammaging in the gingival epithelium through inflammasomes activation.

BACKGROUND AND OBJECTIVE: Diabetes accelerates inflammaging in various tissue with an increase in senescent cell burden and senescence-associated secretory phenotype (SASP) secretion, which is a significant cause of tissue dysfunction and contributes to the diabetic complications. Recently, inflammasomes are thought to contribute to inflammaging. Here, utilizing diabetic models in vivo and in vitro, we investigated the potential association between hyperglycemia-induced inflammaging and gingival tissue dysfunction and the mechanism underlying inflammasome-associated inflammaging. MATERIALS AND METHODS: Gingival epithelium and serum were collected from control and diabetic patients and mice. The expression of p16, p21, and inflammasomes in the gingival epithelium, SASP factors in serum, and the molecular factors associated with gingival epithelial barrier function were assessed. Human oral keratinocyte (HOK) was stimulated with normal and high glucose, and pre-treated with Z-YVAD-FMK (Caspase-1 inhibitor) prior to evaluating cellular senescence, SASP secretion, and inflammasome activation. RESULTS: In vivo, hyperglycemia significantly elevated the local burden of senescent cells in the gingival epithelium and SASP factors in the serum and simultaneously reduced the expression levels of Claudin-1, E-cadherin, and Connexin 43 in the gingival epithelium. Interestingly, the inflammasomes were activated in the gingival epithelium. In vitro, high glucose-induced the inflammaging in HOK, and blocking inflammasome activation through inhibiting Caspase-1 and glucose-induced inflammaging. CONCLUSIONS: Hyperglycemia accelerated inflammaging in the gingival epithelium through inflammasomes activation, which is potentially affiliated with a decline in the gingival epithelial barrier function in diabetes. Inflammasomes-related inflammaging may be the crucial mechanism underlying diabetic periodontitis and represents significant opportunities for advancing prevention and treatment options.

Interrelated role of Klotho and calcium-sensing receptor in parathyroid hormone synthesis and parathyroid hyperplasia.

The pathogenesis of parathyroid gland hyperplasia is poorly understood, and a better understanding is essential if there is to be improvement over the current strategies for prevention and treatment of secondary hyperparathyroidism. Here we investigate the specific role of Klotho expressed in the parathyroid glands (PTGs) in mediating parathyroid hormone (PTH) and serum calcium homeostasis, as well as the potential interaction between calcium-sensing receptor (CaSR) and Klotho. We generated mouse strains with PTG-specific deletion of Klotho and CaSR and dual deletion of both genes. We show that ablating CaSR in the PTGs increases PTH synthesis, that Klotho has a pivotal role in suppressing PTH in the absence of CaSR, and that CaSR together with Klotho regulates PTH biosynthesis and PTG growth. We utilized the tdTomato gene in our mice to visualize and collect PTGs to reveal an inhibitory function of Klotho on PTG cell proliferation. Chronic hypocalcemia and ex vivo PTG culture demonstrated an independent role for Klotho in mediating PTH secretion. Moreover, we identify an interaction between PTG-expressed CaSR and Klotho. These findings reveal essential and interrelated functions for CaSR and Klotho during parathyroid hyperplasia.

Experimental investigation on the long-term behaviour of prefabricated timber-concrete composite beams with steel plate connections.

This paper presents the results of long-term experiments performed on three timber-concrete composite (TCC) beams. An innovative fabricated steel plate connection system, which consists of screws and steel plates embedded in concrete slabs, was adopted in the TCC beam specimens. The adopted shear connection can provide dry-type connection for TCC beams. Steel plates were embedded in concrete slabs while the concrete slab was constructed in factories. The timber beam and concrete slab can be assembled together using screws at the construction site. In this experimental programme, the beam specimens were subjected to constant loading for 613 days in indoor uncontrolled environments. The influence of long-term loading levels and the number of shear connections on the long-term performance of TCC beams was investigated and discussed. The mid-span deflection, timber strain, and interface relative slip at the positions of both connections and beam-ends were recorded throughout the long-term tests. It was found the long-term deflection of the TCC beam increased by approximately 60% while the long-term loads were doubled. Under the influence of the variable temperature and humidity, the TCC specimens with 8 shear connections showed slighter fluctuations compared with the TCC beam with 6 shear connections. In the 613-day observation period, the maximum deflection increment recorded was 6.56 mm for the specimen with eight shear connections and 20% loading level. A rheological model consisting of two Kelvin bodies was employed to fit the curves of creep coefficients. The final deflections predicted of all specimens at the end of 50-year service life were 2.1~2.7 times the initial deflections caused by the applied loads. All beam specimens showed relative small increments in mid-span deflection, strain and relative slip over time without any degradations, demonstrating the excellent long-term performance of TCC beams using the innovative steel plate connection system, which is also easily fabricated.

[Design of Portable EEG and Blood Oxygen Synchronous Acquisition System].

In order to obtain comprehensive brain activity information conveniently in real time, this study designs a portable EEG and blood oxygen synchronous acquisition system for real-time monitoring of brain functional activities. The EEG electrodes filter and amplify the detected EEG signals, and send them to the microprocessor via Bluetooth to analyze the EEG data; the photoelectric probe converts the optical signals into electrical signals, which are amplified and separated, filtered, and AD converted, calculates the brain's oxygenation and blood-red protein (ΔHbO2) and blood-red protein (ΔHb) by amplification of Lambert-Beer law. Finally, experiments with commercial instruments NuAmps and Oximeter show that the system can calculate ΔHbO2 and ΔHb while collecting EEG signals.

Endogenous GDF11 regulates odontogenic differentiation of dental pulp stem cells.

Dental stem cell-based tooth regeneration is the futuristic treatment for missing teeth. Growth differentiation factor 11 (GDF11), a novel member of the TGF-beta superfamily, has been reported to play a critical role in regulating stem cell differentiation. However, the role of endogenous GDF11 during dental stem cell differentiation remains unknown. Here, we have shown that GDF11 was highly expressed in dental pulp tissues in both mouse and human. Knockdown of endogenous GDF11 in human dental pulp stem cells (hDPSCs) led to comparable proliferation and migration but attenuated odontogenic differentiation as evidenced by alkaline phosphatase and Alizarin Red S staining. In addition, transcriptional levels of odontogenic-related genes were significantly down-regulated according to real-time polymerase chain reaction. Mechanistically, we performed RNA sequencing analysis and found that silencing of endogenous GDF11 compromised the process of ossification and osteoblast differentiation, especially down-regulated transcription expression of Wnt pathway-specific genes. Immunofluorescence staining also showed diminished ß-catenin expression and nuclei accumulation after knockdown of endogenous GDF11 in hDPSCs. In summary, our results suggested that endogenous GDF11 positively regulate odontogenic differentiation of hDPSCs through canonical Wnt/ß-catenin signalling pathway.

Effect and Molecular Mechanisms of Collateral Vessel Growth Mediated by Activation of Transient Receptor Potential Vanilloid Type 1.

Information on the function of transient receptor potential vanilloid 1 (TRPV1) in arteriogenesis is limited. We aimed to verify whether TRPV1 is involved in collateral vessel growth in rat hind limbs and elucidate the possible subcellular action mechanisms. Adult Sprague Dawley rats were chosen to establish the hind limb ischemic model and treatment with capsaicin. Angiographies were performed, and tissue was isolated for immunohistochemistry. In vitro, rat aortic endothelial cells (RAECs) were treated with capsaicin and antagonist capsazepine. The RAEC proliferation was determined, and the protein and mRNA levels of Ca2+-dependent transcription factors were assessed. In vivo, the collateral vessels exhibited positive outward remodeling characterized by enhanced inflammatory cell/macrophage accumulation in the adventitia and activated cell proliferation in all layers of the vascular wall and elevated endothelial NO synthetase expression in the rats with hind limb ligation. In RAECs, TRPV1 activation-induced Ca2+-dependent transcriptional factors, nuclear factor of activated T cells 1, calsenilin and myocyte enhancer factor 2C increase, and augmented RAEC proliferation could be a subcellular mechanism for TRPV1 in endothelial cells and ultimately contribute to collateral vessel growth. TRPV1, a novel candidate, positively regulates arteriogenesis, meriting further studies to unravel the potential therapeutic target leading to improved collateral vessel growth for treating ischemic diseases.

A kinetic/thermodynamic study of transparent co-adsorbents and colored dye molecules in visible light based on microgravimetric quartz-crystal microbalance on porous TiO2 films for dye-sensitized solar cells.

In this study, a quartz crystal microbalance (QCM) in situ method is used to study the kinetic and thermodynamic processes of the adsorption of ruthenium-based dyes (N719, N3, N749), and the co-adsorbent chenodeoxycholic acid (CDCA) on the TiO2 film surface. The results of the kinetic studies show that the adsorption rate of N749 is slightly higher than the other two dyes, and the adsorption rate of CDCA is more sensitive to temperature change. The adsorption mechanism of the dye and CDCA on the surface of TiO2 can be reasonably inferred based on the result of the activation energy. The isotherm adsorption model studies show that the ratio of the number of surface molecules (296 K) is n(N719) : n(N3) : n(N749) : n(CDCA) = 0.69 : 1.48 : 0.50 : 1. The Keq value of CDCA is about two orders of magnitude smaller than that of all the dye molecules, which indicates that the adsorption strength of CDCA is much weaker than that of the dye molecules. Thermodynamic studies show that the adsorption reaction is an endothermic reaction. The ΔS is ΔS(N3 = 143.11 J mol-1) > ΔS(N719 = 112.72 J mol-1) > ΔS(N749 = 109.43 J mol-1) > ΔS(CDCA = 96.14 J mol-1). The Gibbs free energy ΔG is negative, and indicates that the adsorption reaction of the four molecules on the surface of the TiO2 film is spontaneous. The results of this paper show that the tedious and lengthy experimental process of the traditional method can be simplified by QCM. In addition, the development of this study provides a certain theoretical and experimental basis for future studies on the interaction mechanism between dyes and co-adsorbents.

An in situ exchange mechanism for dye molecules and cations at the nano-semiconductor film/electrolyte interface.

This communication uses electrochemical quartz crystal microbalance (EQCM) in combination with the potentiostatic method to study the in situ exchange mechanism for dye molecules and cations on the nano-film surface under a constant potential. The relationship between dye molecule desorption mass and charge was analyzed. A theoretical model was established to obtain the important parameters of cation exchange number and apparent valence electron number during dye desorption, and the microscopic desorption mechanism of the dye is further revealed.

[Current Advances in Peri-implantitis Mouse Model].

Peri-implantitis is the most common and intractable complication of dental implant-supported prothesis affecting its long-term success, and is one of the main reasons for implant failure. Due to the limitation of the research methods, the pathogenesis and pathological processes of peri-implantitis remain unclear. Animal models are indispensable tools to study the pathogenesis of diseases. With the advances of the dental implants, the peri-implantitis mouse model has been used in experimental research. This paper summarized recent studies from the following five aspects: the advantages of the mouse model, the influence of mouse strain, the design of micro-implant, the way of implant insertion, as well as the induction of peri-implantitis, aiming to provide references and help for researchers. Compared with the large animal models of peri-implantitis, the mouse model of peri-implantitis is more flexible in use. Lower costs can better control the sample number and shorter induction time can better control experimental duration. The completion of mouse genome sequencing and the progress of the genetic operating system also make the pathogenetic study possible. However, the mouse model of peri-implantitis still has some limitations. Limited by the small size of mouse oral cavity, implant insertion surgery is technically demanding, and complex surgeries are even more challenging. Moreover, due to short history of the peri-implantitis mouse model, its corresponding technical theories such as implantation methods, peri-implantitis induction methods and so on are not unified yet and still need further research and development.

Coexistence of oscillation and quenching states: Effect of low-pass active filtering in coupled oscillators.

Effects of a low-pass active filter (LPAF) on the transition processes from oscillation quenching to asymmetrical oscillation are explored for diffusively coupled oscillators. The low-pass filter part and the active part of LPAF exhibit different effects on the dynamics of these coupled oscillators. With the amplifying active part only, LPAF keeps the coupled oscillators staying in a nontrivial amplitude death (NTAD) and oscillation state. However, the additional filter is beneficial to induce a transition from a symmetrical oscillation death to an asymmetrical oscillation death and then to an asymmetrical oscillation state which is oscillating with different amplitudes for two oscillators. Asymmetrical oscillation state is coexisting with a synchronous oscillation state for properly presented parameters. With the attenuating active part only, LPAF keeps the coupled oscillators in rich oscillation quenching states such as amplitude death (AD), symmetrical oscillation death (OD), and NTAD. The additional filter tends to enlarge the AD domains but to shrink the symmetrical OD domains by increasing the areas of the coexistence of the oscillation state and the symmetrical OD state. The stronger filter effects enlarge the basin of the symmetrical OD state which is coexisting with the synchronous oscillation state. Moreover, the effects of the filter are general in globally coupled oscillators. Our results are important for understanding and controlling the multistability of coupled systems.